scholarly journals Insights into the genetic architecture of the human face

2020 ◽  
Author(s):  
Julie D. White ◽  
Karlijne Indencleef ◽  
Sahin Naqvi ◽  
Ryan J. Eller ◽  
Jasmien Roosenboom ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Genetic Architecture ◽  
Cell Types ◽  
Human Face ◽  
Normal Range ◽  
Enhancer Activity ◽  
Limb Morphogenesis ◽  
Cranial Neural Crest Cells ◽  
Genomic Regions

AbstractThe human face is complex and multipartite, and characterization of its genetic architecture remains intriguingly challenging. Applying GWAS to multivariate shape phenotypes, we identified 203 genomic regions associated with normal-range facial variation, 117 of which are novel. The associated regions are enriched for both genes relevant to craniofacial and limb morphogenesis and enhancer activity in cranial neural crest cells and craniofacial tissues. Genetic variants grouped by their contribution to similar aspects of facial variation show high within-group correlation of enhancer activity, and four SNP pairs display evidence of epistasis, indicating potentially coordinated actions of variants within the same cell types or tissues. In sum, our analyses provide new insights for understanding how complex morphological traits are shaped by both individual and coordinated genetic actions.

scholarly journals Genome-wide regulatory model from MPRA data predicts functional regions, eQTLs, and GWAS hits

2017 ◽  
Author(s):  
Yue Li ◽  
Alvin Houze Shi ◽  
Ryan Tewhey ◽  
Pardis C. Sabeti ◽  
Jason Ernst ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Association Studies ◽  
Cell Types ◽  
Sequence Information ◽  
Regulatory Sequences ◽  
Genome Wide Association Studies ◽  
Regulatory Activity ◽  
Enhancer Activity ◽  
Genome Wide ◽  
Genomic Regions

Massively-parallel reporter assays (MPRA) enable unprecedented opportunities to test for regulatory activity of thousands of regulatory sequences. However, MPRA only assay a subset of the genome thus limiting their applicability for genome-wide functional annotations. To overcome this limitation, we have used existing MPRA datasets to train a machine learning model that uses DNA sequence information, regulatory motif annotations, evolutionary conservation, and epigenomic information to predict genomic regions that show enhancer activity when tested in MPRA assays. We used the resulting model to generate global predictions of regulatory activity at single-nucleotide resolution across 14 million common variants. We find that genetic variants with stronger predicted regulatory activity show significantly lower minor allele frequency, indicative of evolutionary selection within the human population. They also show higher over-lap with eQTL annotations across multiple tissues relative to the background SNPs, indicating that their perturbations in vivo more frequently result in changes in gene expression. In addition, they are more frequently associated with trait-associated SNPs from genome-wide association studies (GWAS), enabling us to prioritize genetic variants that are more likely to be causal based on their predicted regulatory activity. Lastly, we use our model to compare MPRA inferences across cell types and platforms and to prioritize the assays most predictive of MPRA assay results, including cell-dependent DNase hypersensitivity sites and transcription factors known to be active in the tested cell types. Our results indicate that high-throughput testing of thousands of putative regions, coupled with regulatory predictions across millions of sites, presents a powerful strategy for systematic annotation of genomic regions and genetic variants.

scholarly journals Genetic Variants of the NF-κB Pathway: Unraveling the Genetic Architecture of Psoriatic Disease

2021 ◽  
Vol 22 (23) ◽  
pp. 13004
Author(s):  
Rubén Queiro ◽  
Pablo Coto-Segura ◽  
Leire González-Lara ◽  
Eliecer Coto
Keyword(s):  
Genetic Variants ◽  
Genetic Architecture ◽  
Genetic Basis ◽  
Genetic Factors ◽  
Disease Susceptibility ◽  
Cell Types ◽  
Psoriatic Disease ◽  
Pharmacological Response ◽  
Light Chain Enhancer ◽  
Shared Genetic

Psoriasis is a multifactorial genetic disease for which the genetic factors explain about 70% of disease susceptibility. Up to 30–40% of psoriasis patients develop psoriatic arthritis (PsA). However, PsA can be considered as a “disease within a disease”, since in most cases psoriasis is already present when joint complaints begin. This has made studies that attempt to unravel the genetic basis for both components of psoriatic disease enormously difficult. Psoriatic disease is also accompanied by a high burden of comorbid conditions, mainly of the cardiometabolic type. It is currently unclear whether these comorbidities and psoriatic disease have a shared genetic basis or not. The nuclear factor of kappa light chain enhancer of activated B cells (NF-κB) is a transcription factor that regulates a plethora of genes in response to infection, inflammation, and a wide variety of stimuli on several cell types. This mini-review is focused on recent findings that highlight the importance of this pathway both in the susceptibility and in the determinism of some features of psoriatic disease. We also briefly review the importance of genetic variants of this pathway as biomarkers of pharmacological response. All the above may help to better understand the etiopathogenesis of this complex entity.

scholarly journals Revealing the transcription factor regulatory context of human specific cortical development using single-cell multi-omics

2021 ◽  
Author(s):  
Yan Wu ◽  
Blue Lake ◽  
Brandon Sos ◽  
Song Chen ◽  
Thu E. Duong ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Human Brain ◽  
Single Cell ◽  
Target Genes ◽  
Cell Types ◽  
Chromatin Interaction ◽  
Specific Sequence ◽  
Enhancer Activity ◽  
Genomic Regions ◽  
Human Specific

AbstractHuman behaviors are at least partially driven by genomic regions that influence human-specific neurodevelopment. This includes genomic regions undergoing human specific sequence acceleration (Human Accelerated Regions or HARs) and regions showing human-specific enhancer activity (Human Gained Enhancers or HGEs) not present in other primates. However, prior studies on HAR/HGE activities involved mixtures of brain cell types and focused only on putative downstream target genes. Here, we directly measured cell type specific HAR/HGE activity in the developing fetal human brain using two independent single-cell chromatin accessibility datasets with matching single-cell gene expression data. Transcription factor (TF) motif analyses identified upstream TFs binding to HARs/HGEs and identified LHX2, a key regulator of forebrain development, as an active HGE regulator in neuronal progenitors. We integrated our TF motif analyses with published chromatin interaction maps to build detailed regulatory networks where TFs are linked to downstream genes via HARs/HGEs. Through these networks, we identified a potential regulatory role for NFIC in human neuronal progenitor networks via modulating the Notch signaling and cell adhesion pathways. Therefore, by using a single cell multi-omics approach, we were able to capture both the upstream and downstream regulatory context of HARs/HGEs, which may provide a more comprehensive picture of the roles HARs/HGEs play amongst diverse fetal cell types of the developing human brain.

scholarly journals 3D facial phenotyping by biometric sibling matching used in contemporary genomic methodologies

PLoS Genetics ◽  
2021 ◽  
Vol 17 (5) ◽  
pp. e1009528
Author(s):  
Hanne Hoskens ◽  
Dongjing Liu ◽  
Sahin Naqvi ◽  
Myoung Keun Lee ◽  
Ryan J. Eller ◽  
...  
Keyword(s):  
Genetic Architecture ◽  
Complex Nature ◽  
Normal Range ◽  
Active Chromatin ◽  
One Dimensional ◽  
Biologically Relevant ◽  
Facial Shape ◽  
Genome Wide ◽  
Significant Heritability ◽  
Cranial Neural Crest Cells

The analysis of contemporary genomic data typically operates on one-dimensional phenotypic measurements (e.g. standing height). Here we report on a data-driven, family-informed strategy to facial phenotyping that searches for biologically relevant traits and reduces multivariate 3D facial shape variability into amendable univariate measurements, while preserving its structurally complex nature. We performed a biometric identification of siblings in a sample of 424 children, defining 1,048 sib-shared facial traits. Subsequent quantification and analyses in an independent European cohort (n = 8,246) demonstrated significant heritability for a subset of traits (0.17–0.53) and highlighted 218 genome-wide significant loci (38 also study-wide) associated with facial variation shared by siblings. These loci showed preferential enrichment for active chromatin marks in cranial neural crest cells and embryonic craniofacial tissues and several regions harbor putative craniofacial genes, thereby enhancing our knowledge on the genetic architecture of normal-range facial variation.

Comparison of Immunological and Functional Assays for Measurement of Soluble Fibrin

1995 ◽  
Vol 74 (02) ◽  
pp. 673-679 ◽  
Author(s):  
C E Dempfle ◽  
S A Pfitzner ◽  
M Dollman ◽  
K Huck ◽  
G Stehle ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Low Grade ◽  
Plasma Samples ◽  
Normal Range ◽  
Soluble Fibrin ◽  
Discriminating Power ◽  
Fibrin Monomer ◽  
Cerebral Ischemic

SummaryVarious assays have been developed for quantitation of soluble fibrin or fibrin monomer in clinical plasma samples, since this parameter directly reflects in vivo thrombin action on fibrinogen. Using plasma samples from healthy blood donors, patients with cerebral ischemic insult, patients with septicemia, and patients with venous thrombosis, we compared two immunologic tests using monoclonal antibodies against fibrin-specific neo-epitopes, and two functional tests based on the cofactor activity of soluble fibrin complexes in tPA-induced plasminogen activation. Test A (Enzymun®-Test FM) showed the best discriminating power among normal range and pathological samples. Test B (Fibrinostika® soluble fibrin) clearly separated normal range from pathological samples, but failed to discriminate among samples from patients with low grade coagulation activation in septicemia, and massive activation in venous thrombosis. Functional test C (Fibrin monomer test Behring) displayed good discriminating power between normal and pathological range samples, and correlated with test A (r = 0.61), whereas assay D (Coa-Set® Fibrin monomer) showed little discriminating power at values below 10 μg/ml and little correlation with other assays. Standardization of assays will require further characterization of analytes detected.

A Deficiency Screen for Zygotic Loci Required for Establishment and Patterning of the Epidermis in Caenorhabditis elegans

Genetics ◽  
1997 ◽  
Vol 146 (1) ◽  
pp. 185-206 ◽  
Author(s):  
Rebecca M Terns ◽  
Peggy Kroll-Conner ◽  
Jiangwen Zhu ◽  
Sooyoun Chung ◽  
Joel H Rothman
Keyword(s):  
Caenorhabditis Elegans ◽  
Cell Types ◽  
Epidermal Cells ◽  
Epidermal Differentiation ◽  
Apparent Effect ◽  
Internal Organs ◽  
C Elegans ◽  
Seam Cell ◽  
Genomic Regions ◽  
Caenorhabditis Elegans Genome

To identify genomic regions required for establishment and patterning of the epidermis, we screened 58 deficiencies that collectively delete at least ∼67% of the Caenorhabditis elegans genome. The epidermal pattern of deficiency homozygous embryos was analyzed by examining expression of a marker specific for one of the three major epidermal cell types, the seam cells. The organization of the epidermis and internal organs was also analyzed using a monoclonal antibody specific for epithelial adherens junctions. While seven deficiencies had no apparent effect on seam cell production, 21 were found to result in subnormal, and five in excess numbers of these cells. An additional 23 deficiencies blocked expression of the seam cell marker, in some cases without preventing cell proliferation. Two deficiencies result in multinucleate seam cells. Deficiencies were also identified that result in subnormal numbers of epidermal cells, hyperfusion of epidermal cells into a large syncytium, or aberrant epidermal differentiation. Finally, analysis of internal epithelia revealed deficiencies that cause defects in formation of internal organs, including circularization of the intestine and bifurcation of the pharynx lumen. This study reveals that many regions of the C. elegans genome are required zygotically for patterning of the epidermis and other epithelia.

Effect and in silico characterization of genetic variants associated with severe spermatogenic disorders in a large Iberian cohort

Andrology ◽  
2021 ◽  
Author(s):  
Miriam Cerván‐Martín ◽  
Lara Bossini‐Castillo ◽  
Rocío Rivera‐Egea ◽  
Nicolás Garrido ◽  
Saturnino Luján ◽  
...  
Keyword(s):  
Genetic Variants ◽  
In Silico ◽  
In Silico Characterization

scholarly journals Chromosomal Map of the Model LegumeLotus japonicus

Genetics ◽  
2002 ◽  
Vol 161 (4) ◽  
pp. 1661-1672 ◽  
Author(s):  
Andrea Pedrosa ◽  
Niels Sandal ◽  
Jens Stougaard ◽  
Dieter Schweizer ◽  
Andreas Bachmair
Keyword(s):  
Repetitive Sequences ◽  
Lotus Japonicus ◽  
Chromosome Complement ◽  
Linkage Groups ◽  
Closely Related Species ◽  
F1 Hybrid ◽  
Bac Clones ◽  
Genomic Regions ◽  
Chromosomal Map

AbstractLotus japonicus is a model plant for the legume family. To facilitate map-based cloning approaches and genome analysis, we performed an extensive characterization of the chromosome complement of the species. A detailed karyotype of L. japonicus Gifu was built and plasmid and BAC clones, corresponding to genetically mapped markers (see the accompanying article by Sandal  et al. 2002, this issue), were used for FISH to correlate genetic and chromosomal maps. Hybridization of DNA clones from 32 different genomic regions enabled the assignment of linkage groups to chromosomes, the comparison between genetic and physical distances throughout the genome, and the partial characterization of different repetitive sequences, including telomeric and centromeric repeats. Additional analysis of L. filicaulis and its F1 hybrid with L. japonicus demonstrated the occurrence of inversions between these closely related species, suggesting that these chromosome rearrangements are early events in speciation of this group.

scholarly journals Morphological and Ultrastructural Characterization of Hemocytes in an Insect Model, the Hematophagous Dipetalogaster maxima (Hemiptera: Reduviidae)

Insects ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 640
Author(s):  
Natalia R. Moyetta ◽  
Fabián O. Ramos ◽  
Jimena Leyria ◽  
Lilián E. Canavoso ◽  
Leonardo L. Fruttero
Keyword(s):  
Cell Biology ◽  
Cell Types ◽  
Transmission Electron ◽  
Ultrastructural Characterization ◽  
Current Classification ◽  
Contrast Microscopy ◽  
First Time ◽  
Controversial Aspect

Hemocytes, the cells present in the hemolymph of insects and other invertebrates, perform several physiological functions, including innate immunity. The current classification of hemocyte types is based mostly on morphological features; however, divergences have emerged among specialists in triatomines, the insect vectors of Chagas’ disease (Hemiptera: Reduviidae). Here, we have combined technical approaches in order to characterize the hemocytes from fifth instar nymphs of the triatomine Dipetalogaster maxima. Moreover, in this work we describe, for the first time, the ultrastructural features of D. maxima hemocytes. Using phase contrast microscopy of fresh preparations, five hemocyte populations were identified and further characterized by immunofluorescence, flow cytometry and transmission electron microscopy. The plasmatocytes and the granulocytes were the most abundant cell types, although prohemocytes, adipohemocytes and oenocytes were also found. This work sheds light on a controversial aspect of triatomine cell biology and physiology setting the basis for future in-depth studies directed to address hemocyte classification using non-microscopy-based markers.

scholarly journals Connectivity characterization of the mouse basolateral amygdalar complex

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Houri Hintiryan ◽  
Ian Bowman ◽  
David L. Johnson ◽  
Laura Korobkova ◽  
Muye Zhu ◽  
...  
Keyword(s):  
Granular Cell ◽  
Cell Types ◽  
Projection Neurons ◽  
Cell Type ◽  
Connectivity Map ◽  
Analysis Techniques ◽  
Domain Specific ◽  
Cell Type Specific ◽  
Unique Domain

AbstractThe basolateral amygdalar complex (BLA) is implicated in behaviors ranging from fear acquisition to addiction. Optogenetic methods have enabled the association of circuit-specific functions to uniquely connected BLA cell types. Thus, a systematic and detailed connectivity profile of BLA projection neurons to inform granular, cell type-specific interrogations is warranted. Here, we apply machine-learning based computational and informatics analysis techniques to the results of circuit-tracing experiments to create a foundational, comprehensive BLA connectivity map. The analyses identify three distinct domains within the anterior BLA (BLAa) that house target-specific projection neurons with distinguishable morphological features. We identify brain-wide targets of projection neurons in the three BLAa domains, as well as in the posterior BLA, ventral BLA, posterior basomedial, and lateral amygdalar nuclei. Inputs to each nucleus also are identified via retrograde tracing. The data suggests that connectionally unique, domain-specific BLAa neurons are associated with distinct behavior networks.

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